WO1992000277A1

WO1992000277A1 - Piperidine derivative

Info

Publication number: WO1992000277A1
Application number: PCT/JP1991/000866
Authority: WO
Inventors: Yohji Ezure; Shigeaki Maruo; Katsunori Miyazaki; Naoyoshi Yamada
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 1990-06-29
Filing date: 1991-06-27
Publication date: 1992-01-09
Also published as: CA2086413A1; EP0536402A4; EP0536402A1

Abstract

A 3,4,5-trihydroxypiperidine derivative of general formula (I), having a β-galactosidase inhibitory action and therefore usable as a carcinostatic agent, wherein R represents a C1 to C18 saturated or unsaturated hydrocarbon group which may be substituted with a linear, branched or cyclic group.

Description

Specification

Pyridin derivative technology i 37

The present invention relates to a bilidin derivative represented by the following general formula [I].

CH ₂ OH J ^H [I]

In the formula, R represents a saturated hydrocarbon or an unsaturated hydrocarbon having 1 to 18 carbon atoms which may have a linear, branched or cyclic substituent.

Background technology

Bossman et al. Have reported that darcosidase activity, especially / 9-galactosidase activity, is increased in 3T3 fibroblasts transformed with RNA viruses (HB Bosmann et al., Biochem. Biophys. Acta, 264, 339 (1972)). Therefore, a β-galactosidase inhibitor has the potential to be used as an anticancer agent or an inhibitor of pain metastasis, and various studies have been made so far. For example, Japanese Patent Application No. 57-74090; 31238; Japanese Patent Application No. 60-123135; The Journal of Actibiotics, 28, 1006 (1975); the same (3), 212 (1979); the same 1 | (3), 217 (1979).

Disclosure of the invention 9) In order to utilize a galactosidase inhibitor as an analgesic, it can be easily imagined that a substance having a stronger inhibitory activity is more advantageous in terms of dosage, side effects, and the like.

Thus, the present inventors conducted a study with a primary objective of finding a compound having a stronger inhibitory activity than a known compound.

The present inventors have conducted intensive studies and found that the 3,4,5-trihydroxybiperidine derivative represented by the above general formula [I] or a pharmacologically acceptable salt thereof has a strong inhibitory activity. And finally completed the present invention. The compound of the present invention is a novel compound not described in the literature.

Here, linear, branched or S-shaped saturated or unsaturated hydrogenated carbons include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-heptyl, π-dodecyl, butyl, teryl, isobrodinyl, butenyl, hebutenyl, decenyl, ethur, probutur, cyclopropylmethyl, cyclobutylmethyl, cyclopentyl methyl, Cyclohexylmethyl, cyclopropylmethyl, cyclobutenylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, pendyl and the like can be mentioned.

Substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, heptyl, peroxyacid group, cyano, fluorine, chlorine, bromine, iodine, niobium Toro, Nitroso, Formyl, Acetyl, α-Pionyl, Hexanoyl, Lauroyl, Penzol, Toluoyl, Cinnamoyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, Butoxy, pentyloxy, phenoxy, penziloxy, methylenedioxy, ethylenedioxy, propoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, formyloxy, acetoxy, benzoyloxy, amino, methylamino, dimethylamino, dimethylamino, dimethylamino , Acetylamino, acetylmethylamino, acetylamino, benzoylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, acetylmethylamino, sulfo, sulfamoyl, sulfolomi. , Carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethi-carnomoyl, getylkarha * moir, probirukarha * moir, butyrcarnomoylゥ Raid, methyl raido, dimethyl ureid, ethyl raido, getyl raido, ethi J ri methyl raid, ferul raid, choi raid, methylthioureido, dimethylthio raid, ethyl thiolaido, jetithio , Ethyl methyl thiolaido, phenyl thiolaido, guanidino, etc., and phenyl, phenoxy, tosyl, cyclopropyl, cyclopropyl, which may be substituted on at least one of the above substituents. Robutyl, cyclopentyl, cyclo D-hexyl, cyclopropenyl, cyclobutenyl, cyclopentyl, cyclohexenyl, pyrrolyl, chenyl, frijle, theonil, viridyl, biperidino, biぺ Rizil, morphoyl, quinolyl, indril, phthalate Mi De, Ru can be exemplified Ryoji Li Roh and the like. Furthermore, D- / 3-D-Darco bilanosyl, S- / 9-D-Darco bilanosyl and the like can also be mentioned as substituents. In addition, pharmacologically acceptable salts include metal salts such as lithium salt, sodium salt, potassium salt, calcium salt, etc., ethanol salt, and ethanol salt. Salts of inorganic acids such as salts of organic bases, hydrochlorides, sulfates, phosphates, etc., sulphates, methansulfonates, succinates, lactates, fumarates, maleates, etc. And the like of organic acid salts.

The compound of the present invention may be used as an inhibitor of an enzyme relating to galactose processing in the sugar chain of a glycoprotein, and may be used as a research reagent for glycoprotein sugar chain processing or a sugar chain processing reagent. Dalcosidase inhibitors, such as castanospermine and 1-deoxynojirimysin, have antiviral effects (Fleet et al., PBBS Lett. 237, 128 (1988)), and have an inhibitory effect on pain cell migration (G. Pulverer et al.. J. Cancer. Res. Clin. Oncol, 114, 217 (1988)) or have an immunomodulatory effect and are expected as a drug having such an effect.

Further, food, for example, sugar, potato, juice, beer, chocolate, jam, candy and the like can be added with one or more effective amounts of the compound of the present invention to improve the preservability.

The gist of the present invention lies in the above compound [I] itself.

Specific examples of the compound of the present invention include N-methyl-11-doxygalactostatin, N-ethyl-11-doxygalactostatin, N-propyl-11-doxygalactostatin, N- (2,3-dimethylbutyl) 1-111 Deoxygalactostatin, N— (2,2,3—trimethylpentyl) 1-1-Doxygalactostatin, N—tert-butyl-1-1-dexoxygalactostatin Lactostatin, N— n—pentyl-1-deoxygalactostatin, N—isopentyl-deoxygalactostatin, N-sec 1-pentyl-1-deoxygalactostatin, N—

(3-ethyl-2-isopropylpyrpentyl) 1-year-old xygalactostatin, N-hexyl-1-deoxygalactostatin, N-hexyl-1-dexoxygalactostatin, N-isohexyl-1-dexgalactostatin, N-yl So-heptyl-1-dexoxygalactostatin, N-octyl-1-deoxygalactostatin, N-isooctyl-1-deoxygalactostatin, N-decyl-1-deoxygalactostatin, N-dodecyl-1-dexgalactostatin, N-tetradecalactyl-N-tetradecylactate Xadecyl 1-dexoxygalactostatin, N-octadecylone 1-doxygalactostatin, N-cyclopropylmethyl-1-dexoxygalactostatin, N-cyclopentylmethyl 1 Dokishigaraku Tosutachin, N- consequent Roeki Shirumechiru 1 one Dokishigaraku Tosutachin, N- (2-arsenate Dorokishechiru) Single 1 Dokishigaraku Tosutachin, N- (3 over human Dorokishipuro building) - 1 Dowishigaraku Tosutachin,

N— (4-hydroxybutyl) 1-1-doxygalactostatin, N— (5-hydroxypentyl) -11-doxygalactostatin, N— (2-hydroxy-3-methylbutyl) 1-1-doxygalactostatin, N— (2,3-dihydroxylipuvir) 1-1-Doxygalactostatin, N— (2-Methoxyxetil) 1-1-Doxygalactostatin, N— (2-Proboxixil) 1-1-Doxygalactostatin, N- (2-acetoxityl) 1-1-Doxygalactostatin, N— (4-Penzoyloxyptyl) 1-1-Doxygalactostatin, N— (2-amino) Ethyl) 1-11 Deoxygalactostatin, N— (2-Dimethylaminoethyl) 1-1 Deoxygalactostatin, N— (2-Acetylaminoethyl) 1-1 Deoxygalactostatin, N— (2-Benzoylaminoethyl) 1-doxygalact tostatin,

N— (2-propoxycarbonylaminoethyl) 1-1-deoxygalactostatin, N— (2- (Ν ', N'—cetylmethyl) aminoethyl) 111-doxygalactostatin, Ν—

(2- (Ν'-methylureido) ethyl) 1-11-Doxygalactostatin, Ν— (2- (Ν'-XXnylureido) ethyl) 1-1-Doxygalactostatin, Ν— (2- (Ν, methylthio) 1-Doxygalactostatin, 1-Doxygalactostatin, Ν- (2- (Ν'-fluorothiol) ethyl) -11-Doxygalactostatin, N— (3-Aminobactyl) 1-1-Doxygalactostatin, N— (3-acetylaminobutyral pill) 1-1-Doxygalactostatin, N— (3-benzoylaminobutyl building) 1-1-Doxygalactostatin, N— (3-(}-methyl ureide) pro (Pill) 1-11 Deoxygalactostatin, Ν—Cinnamyl- 1—Doxygalactostatin, 2—Fenoxexetil 1-Doxygalactate Stann, Ν— (ρ-ethoxycarbonylphenoxy) ethyl) 1-doxygalactostatin, Ν— (2-benzyl) 1-deoxygalactostatin, N- (3-phenyloxycarbonyl σ-bil) 1-1-deoxygalactostatin, Ν- (4-amino butyl) 1-1-doxygalactostatin, phenyl-deoxygalactostatin , Ν- (2-butenyl) -1-1-doxygalactostatin, Ν- (3-butenyl) -11-deoxygalactostatin, Ν- (5-hexenyl) -111-doxygalactostatin, Ν- (9-decenyl) -11-doxygalact Tostatin, ル -Polymethyl- 1-doxygalactostatin, Ν- (2-Carboxyethyl) 1-1-Doxygalactostatin, Ν-ethoxycarbonyl- 1-Doxygalactostatin, Ν-Lubamoylmethyl-1-deoxygalactostatin, — (Ν'-Ethylcarbamoylmethyl) -1-Doxygalactostatin, Ν— (fT-butylcarbamoylmethyl) -11-Doxygalactostatin, N— (3-Sulfopropyl) 1-1-Doxygalactostatin, N— (3— Sulfamoyl propyl> 1- 1-Doxygalactostatin, N- (0-carboxypentyl) 1- 1-doxygalactostatin, N- (0- 2 to π-pentyl) 1-1-Doxygalactostatin, N- (5-bromo-2-H) 1-Doxygalactostatin, N-benzoylmethyl 1-Doxygalactostatin, N— (4-Hydroxoxy 3-Methoxypendil) 1-1-Doxygalactostatin, Ν— (2-propynyl) 1-de-okizigalactostatin, Ν— (ρ-hydroxypipe Jill) Single 1 Dokishigaraku Tosutachin, Ν 1- (4-hydroxy-3-methoxy5-2-tropendyl) 1-1-Doxygalactostatin, N— (412-ππ-2-sulfobenzyl) 1-1-Doxygalactostatin, N— (2-hydroxy-4 , 6-Dimethoxypentyl) 1-1-Doxygalactostatin, N- (2-Methylthiobenzyl) -11-Doxygalactostatin, Disodidium N— (2,4-Disulfonate Penzil) 1-1-Doxygalactostatin, N— (2-Cu) Row 5-2-tropenzil) 1-11 Deoxygalactostatin, Ν— (2-chloro-6-2 tropenzil) 1-1-Doxygalactostatin, Ν— (4-1 Chloro 3-2-2 σ-benzyl) 1-1-Doxygalactostatin Ν Ν （(5-Coo 2-2 Tropendil) 1 1-Doxygalacto , Ν— (0-bromopentyl) -1-doxygalactostatin, Ν— (ρ-bromopendyl) -11-doxygalactostatin, Ν— (0-mouth-mouthed penzil) 1-1-doxygalactostatin, Ν— (m-chloro Mouth pencil) 1-Doxygalactostatin, N— (ρ-d D Pencil) 1-1-Doxygalactostatin, N— (0—Fluorodil) 1-1-Doxygalactostatin, N— (m-Fluorobenzyl) -11-Doxygalact Tostatin, Ν— (ρ-Fluoro π-pentyl) 1-1 1-Doxygalactostatin, Ν-1 (ο-Nitropentil) 1- 1-Doxygalactostatin, Ν— (4-Hydroxy-3-3-Tropenedil) 1-1-1 Deoxygalactostatin, Ν— (5—Hydroxy 2-2 Trobenzyl) One 1-Dokishigara click Tosutachin, Ν- (m- human de Xipendil) 1-Doxygalactostatin, N— (p-hydroxypentyl) 1-Doxygalactostatin,

N— (0—hydroxypentyl) 1-1-deoxygalactostatin, N— (2,5-dihydroxybenzyl) 1-1-deoxygalactostatin, N— (3,4-dihydroxypentyl) 1-1-doxygalactostatin, N— (P-carboxipendyl) 1-1-Doxygalactostatin, N- (3,4-methylenedioxypentyl) 1-1-doxygalactostatin, N— (3-carboxy-4-hydroxypentyl) 1-1-doxygalactostatin, N— ( 0-Methyl pentyl) 1- 1-Doxygalactostatin, N- (p-methyl benzyl) 1- 1-Doxygalactostatin, N— (0-Methoxy pendyl) 1- 1-Doxygalactosutin, N— (m-Methoxy benzyl) 1 1-Doxygalact Tostatin, N-I (4-Hydroki -3-methoxypentyl) 1-1-doxygalactostatin, N-(3-hydroxy 4- methoxypentyl)-1-dexgalactostatin, N-(3,4 dimethylbenzyl) 1-dexgalactostatin, N-( p-L-cetylaminopendil) 1-Doxygalactostatin, N- (2,5-dimethylpentyl) 1-1-Doxygalactostatin, N- (0-ethoxypentyl) -1-Doxygalactostatin, N- (2-methyl-methyl) 4-Methoxypentyl) 1-Doxygalactostatin, N— (3,5-Dimethoxypentyl) 1-1-Doxygalactostatin, N- (p-Dimethylaminopentyl) 1-1-Doxygalact Tostatin,: N— (3,4,5-trimethoxybenzyl) -1-deoxygalactostatin, N— (2,4,5-trimethoxybenzyl) 1-1-doxygalactostatin, N— (2,3-epoxy (Provyl) 1-Doxygalactostatin, N— (3-phthalimidoprotyl) 1-1-Doxygalactostatin, N— (2-phthalimidoethyl) 1-1-Doxygalactostatin, N— (2-pyridyl) methyl 1-1-Doxygalactostatin, N— (2— (S—) 5—D—Gluco virano sirou 2-mercapto) ethyl> 1-1-Doxygalata tostatin, N— (2— (0—3—D—Darco viranosil 1) -Doxygalactostatin, N- (2-furyl) methyl-11-Doxygalactostatin, N— (31-indrill) Methyl-1-deoxygalactostatin, N- (2- (5-bromocenyl)) methyl-1-deoxygalactostatin, N- (2-pyrrolyl) methyl-11-deoxygalactostatin, N: (3-pyridyl) methyl-1- Deoxygalactostatin, N- (4-pyridyl) methyl-11-deoxygalactostatin, N-Penziru-1-deoxygalactostatin and the like can be mentioned.

When the compound of the present invention is administered as a drug, the compound of the present invention contains 0.1% to 99.5%, preferably 0.5% to 90% of the compound of the present invention as it is or in a pharmaceutically acceptable nontoxic and inert carrier. The composition is administered to animals, including humans.

As the carrier, one or more solid, semi-solid or liquid diluents, fillers and other prescription auxiliaries are used. Pharmaceutical composition The substance is preferably administered in a unit dosage form. The pharmaceutical composition of the present invention can be administered by injection, intraosseous administration, topical administration (e.g., transdermal administration), or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. For example, microbial administration is particularly preferred.

It is desirable to set the dose of i9-galactosidase inhibitor in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, etc. The amount of the active ingredient of the present invention is generally in the range of 0.1 rog to 3 g Z days / human, preferably in the range of 1 rog to 100 rag / day / human per day. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. Also one day

It is desirable to administer the drug in 1 to 3 divided doses.

For oral administration, solid or liquid dosage units, such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, etc. It can be done depending on the dosage form.

Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance to a suitable fineness and then mixing with a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.

Capsules are prepared by first granulating powders, powders, or tablets as described above. For example, it is produced by filling into a capsule made of a forceps such as a gelatin capsule. Lubricants and glidants, such as colloids such as silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed with the powdered form, and The filling operation can be performed later. Disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substitution hydroxypropyl cellulose, closcarme D-snatrium, carboxystarch sodium, calcium carbonate, sodium carbonate Addition of um, can improve the effectiveness of the medicament when the capsule is ingested.

Also, the fine powder of this product can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and wrapped in a gelatin sheet to prepare a soft capsule. Tablets are made by preparing a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and compressing. The powder mixture is obtained by mixing the appropriately powdered substance with the above-mentioned diluents and pastes and, if necessary, binding agents (eg, carboxymethylcellulose sodium, hydroxypropylcellulose, methylcellulose, hydroxydipropyl). Methylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), dissolution retardant (eg, paraffin, wax, hydrogenated oil, etc.), re-absorbent (eg, tetra-treated salt) ) And adsorbents (eg bentonite, kaolin, dicalcium phosphate, etc.) may also be used in combination. The powder mixture first contains a binder, such as syrup, It can be moistened with starch paste, gum arabic, cellulose solution or polymer solution, and then forced through a sieve to form granules. Instead of granulating the powder in this way, it is also possible to first apply the powder to a tableting machine and then crush the resulting imperfect slag into granules.

The granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid phosphate, talc, mineral oil or the like as a lubricant. The lubricated mixture is then tableted.

Alternatively, the drug may be directly tableted after mixing with a fluid inert carrier without going through the steps of granulation and slag formation as described above. Transparent or translucent protective coatings consisting of sealing shells of SHURAC, coatings of sugar molecular materials, and polishing top coatings of wax can also be used.

Other micro dosage forms, such as solutions, syrups and elixirs, can also be presented in dosage unit form so that a given quantity contains a fixed amount of drug. Silop is produced by dissolving the compound in an appropriate aqueous fragrance solution, and pixil is produced by using a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavor enhancers (eg, palmit oil, saccharin), etc. Can also be added as needed.

If needed, the unit dose formulation for oral administration is It may be encapsulated. The formulation can also provide an extended working time or sustained release by coating or embedding in a polymer or polymer.

Intra-organic administration can be carried out by using a liquid dosage unit form for subcutaneous or intramuscular or intravenous injection, for example, in the form of a drench or suspension. For these, a certain amount of the compound is suspended or dissolved in a non-toxic liquid carrier suitable for the purpose of injection, such as a permanent or oily medium, and the suspension or solution is sterilized. It is manufactured by Alternatively, an aliquot of the compound may be placed in a vial, and the pipette and its contents sterilized and sealed. Spare powders or carriers may be provided with the powder or lyophilized active ingredient for dissolving or mixing immediately prior to administration. Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, stabilizers, preservatives and emulsifiers can be used in combination.

Rectal administration involves administering the compound to a low-sensitivity, permanently soluble or insoluble solid, such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (eg, Witebsol®), 髙 class esters (eg, palmitic acid). (Myristyl ester) and suppositories prepared by dissolving or suspending them in a mixture thereof.

(Synthesis example)

The compound of the present invention can be prepared by a known method, for example, by reductively displacing the hydrogen bonded to the nitrogen of 1-doxygalactostatin [II] with a heplonyl compound and an elongation donor reducing agent. Can be synthesized by a method of directly substituting with the above-mentioned reagents having various substituents or a method of acylating and reducing the nitrogen of formula (3) by a known method. Specifically, the following methods can be cited.

Reducing arrangement

According to the following reaction formula, the compound of the present invention can be prepared by converting compound [Π] into an appropriate solvent, for example, an ice-alcohol mixture, using ketone or aldehyde and a suitable reducing agent, for example, cyanoborohydride. Li metal, Jiarukiruami Roh mullet down, ice fluorinated boron Al force Li alloy厲等, specifically hydrogenation Shiano boron Na Application Benefits U beam (fiaBH ₃ Cf, ice borohydride Na Application Benefits um Z Application Benefits Furuoro It can be obtained by reacting with acetic acid or Raney nickel / hydrogen at 0 to 100 t :.

CHaOH CHaOH

HO one NH R ^l -CH0 J N- CHaR ¹

HO

) H ΌΗ ヽ

NaBH.CN

OH CH, 0H / H ₂ 0 OH

CI) PH4-7

(The above ¹ has the same meaning as for hydrogen, hydroxyl or R.)

Also, according to the Leuekart-Wallach reaction.

Direct replacement

The synthesis of the compound of the present invention by substituting an arsenic directly bonded to nitrogen with a substituent can be carried out according to the following reaction formula. I} is reacted with an alkylating agent (Z—R) and a suitable base, such as potassium carbonate, in a suitable solvent, such as N, N-dimethylformamide (hereinafter “DMF j”). It is carried out by reacting at ~ 100t.

H

(The above R is the same as described above. Z represents an ordinary group in the alkylating agent which is easily oxidized, for example, a halogen such as chlorine, bromine or iodine.)

Reduction of silyl compounds

The synthesis of the compound of the present invention by the reduction of the acyl compound is carried out by reacting the compound [を] in a suitable solvent, for example, ice, a water / alcohol mixture or DMF according to the following reaction formula.

R ² -C0-X) or the corresponding ice-free material (R ³ -C0-0-C0-R ² ) by acylation and reduction with a suitable reducing agent, for example hydrogenated lithium (LiAlfU). Do.

(Next page)

CH ₂ OH

One NCHiR ²

HO

) H ヽ

OH

(The above has the same meaning as for R. X represents a halogen, for example, chlorine, bromine or iodine.)

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention will be described in more detail below with reference to Examples, Reference Examples and Test Examples, but needless to say, the present invention is not limited thereto.

Reference Example 1 Synthesis of N- ______ * ^ oxycarbonylmoranolin 16.3 g (0.1 mol) of moranolin and 8.4 g (0.1 mol) of sodium hydrogencarbonate were added to 160 ml of water and Dissolved in 160 ml of form, added benzyloxycarbonyl chloride (20.47 g, 0.12 mol) under ice-cooling, and stirred vigorously. (0,01 mol) Penzyloxycarbonyl sigma-ride 5.12 g (0.03 mol) was added and reacted for 6 hours, and the pH of the aqueous layer was adjusted to 5-6, and added with an equal amount of chloroform. After performing the extraction twice, the aqueous layer was dried. Ethyl succinate and ethanol (1: 1) were added to the solid to remove insolubles, and the filtrate was dried to obtain 30 g (quantitative) of an oily compound of the present invention.

Reference Example 2 —Synthesis of benzyloxycarbonyl 2,4,6-

29 g (97 mmol) of the compound of Reference Example 1, 3.34 g (19 mmol) of eternal toluenesulfonic acid, 29.4 g (194 mmol) of pentaaldehyde dimethyl acetal, and 29 g of active calcium sulfate were added to 290 ra £ of DMF. For 24 hours. The reaction solution is neutralized by adding a strong clay-based ion exchange resin (Diaion SA-11A0H- type). After passing through the insolubles, the solution is dried and crystallized with ethyl acetate and hexane. Thus, 29 g (yield: 72%) of the present compound as an amorphous substance was obtained. At break points 134-138.

Reference Example 3 Synthesis of N-Penziloxycarbone 2,3-di-O-Penziru 4,4__6-1-0_-benzylidenemoranoline 27 g (70 mmol) of the compound of Reference Example 2 and 60% hydrogenated 21 g (875 mol) of tritium was added to DMF100 mg, and the mixture was stirred for 30 minutes. Then, 170 g (995 mimol) of benzylbutemide was added dropwise under ice-cooling and allowed to stand for two days. After standing, methanol was added, the reaction mixture was dried, and the oily substance obtained was dissolved in chloroform, extracted several times with water, and the chloroform layer was dried. Then, the resulting product was applied to the obtained gel-like product (ヮ -gel C-200) and eluted with hexane-ethyl acetate (9: 1) to give an oily book. 37.5 g (yield 94%) of the compound was obtained. Reference Example 4 N—Penziloxycarbone 2, _ 3—Gee 0 Synthesis of 1-Pendylmoranoline

36.5 g (64 mmol) of the compound of Reference Example 3 was dissolved in 320 mL of acetic acid and 80 mL of elongate, and the mixture was stirred at 60 t for 6 hours. After stirring, the reaction solution was dried to obtain 36.3 g of an oily substance containing the present compound. REFERENCE EXAMPLE 5 Synthesis of N, 6-0-potassium 2.3-Gee 0-benzylmolanolin 36.3 g of oily substance containing the compound of reference example 4 and 40 g of carbon dioxide paste were added to 360 m of methanol. Melted in 40 ml of ice and stirred at 60 for 4 hours. After stirring, the reaction solution was dried, and the obtained solid was dissolved in chloroform and extracted several times with water. Then, the foam layer was dried and crystallized with ethyl acetate and hexane to obtain 19 g of an amorphous substance. Cut point 110 ~ lil t :.

Reference example 6 N, 6— 0—force Luba moiré 2, 3—gee 0— ^? Synthesis of Njiru 4-1-0-mesylmolanolin

19 g (51 mimol) of the compound of Reference Example 5 and g! 15.6 g (154 mimol) of ethylamine was dissolved in 200 ml of acetone, and 9.8 g (85 mimol) of mesilicum mouth ride was added dropwise under ice-cooling, followed by stirring for 30 minutes. After stirring, the reaction solution was dried and partitioned with 0.1N hydrochloric acid and ethyl acetate to dry the ethyl acetate layer. Then, the mixture was partitioned between 0.1N sodium borocarbonate and black form and the dry form layer was dried. Then, it was crystallized from ethyl acetate, chloroform and hexane to obtain 22.6 g (yield 98%) of the present compound. Melting point 197-199.

Reference example 7 N, 6-0-force Luba moiré 2, 3-gee ぺぺぺジジ 0 0 ペン — ゾゾゾーラク Synthesis

The compound of Reference Example 6 22. lg (49 mmol) and lithium benzoate (7.54 g, 58 mmol) were dissolved in DMF 30 mL and stirred at 100 t for 2 days. After stirring, the reaction solution was subjected to dry explosion, partitioned with 0.2N sodium hydrogen carbonate and ethyl peroxylate, and the ethyl peroxylate layer was dried to give 24.5 g of an oily compound of the present invention ( Quantitative) was obtained. Then, it was made amorphous with getyl ether. The cut point is 135-137 t.

Reference Example 8 Synthesis of N, 6 _— 0_—Lubamoyl 2,3-Di-1 0—Benzyru 1-Doxygalatatostatin

24 g (50 mmol) of the compound of Reference Example 7 was dissolved in 450 ml of methylene chloride and ethanol, and sodium hydroxide was added.

^ Was added and stirred at 50 t for 3 hours. After stirring, the reaction solution was neutralized by adding concentrated hydrochloric acid, dried, and separated with chloroform and water. Then, the chloroform eyebrows were dried to obtain 20.9 g of an oily substance containing the present compound.

Reference Example 9 3— _Di-1 0—Penziru; Synthesis of I-deoxygalactostatin

20 g of a coil-like substance containing the compound of Reference Example 8 and hydrate of Palladium Peroxide 8 were dissolved in 320 mL of methanol and 80 mg of water, and stirred under reflux for 4 hours. After stirring, dry ice was added to the reaction solution, and the mixture was centrifuged at 8,500 rpm, and the precipitate was washed with methanol and centrifuged again. Then, the supernatants were combined, dried, and partitioned with 0.1N hydrochloric acid and black form. The hydrochloric acid layer was made weakly basic with sodium carbonate, and the present compound was extracted with chill acid. Then, the ethyl acetate layer was dried, and platelets were collected with ethyl acetate and hexane. 11.82 g I got 126-128 t.

Reference Example 10 Synthesis of 1-doxygalactostatin hydrochloride 10 g of the compound of Reference Example 9 was dissolved in liquid ammonia, 2.8 g of metal sodium was added, and the mixture was stirred in acetone-dry ice for 30 minutes. Then, ammonium chloride was added until the blue color of the reaction solution disappeared. Then, ammonia was vaporized, and the remaining solid matter was introduced into a column of strong acid ion exchange resin (Dowex 50WX-2H + type). The solution was eluted with ammonia and dried. Subsequently, the solution was introduced into a column of a strongly basic ion exchange resin (Diaion SA-11A QH- type), and the water-passing solution was dried. Finally, the obtained oily substance was dissolved in ethanol and adjusted to a weak acidity with concentrated hydrochloric acid to obtain 5.26 g (yield 90%) of crystals of the present compound. Melting point 237-239 * 0.

[<<] _D 54.96 (20: C = 0.997, H ₃₀ )

Elemental analysis (as CeUlNih)

Calculated value () C: 36.10 H: 7.07 N: 7.02

Actual measurement (%) C: 35.97 H: 7.09 N: 7.04

Example 1 Synthesis of N-methyl-1-dexoxygalactostatin

0.5 g (2.5 mmol) of 1-dia Φ cigaractostatin hydrochloride, 0.64 g (7.5 mmol) of a 35% formalin solution and 0.16 g (2.5 mmol) of sodium hydrogen cyanoborohydride in 12.5 m of methanol And 2.5 ml of water, the pH was adjusted to 4-5 with glacial acetic acid, and the mixture was stirred at room temperature for 2 hours. After stirring, this solution is converted to a strong acid ion exchange resin (Dowex 50WX-2H + type). The ion-exchange resin was washed with methanol, and the product was dissolved in methanol / ammonia = 10: 1. After evaporating the solvent to dryness using a rotary evaporator, the product is introduced into a strongly basic ion-exchange resin (Diaion SA-11A OH "type), and the appropriate liquid is passed through to dryness. The obtained product was recrystallized from ethanol to give 0.34 g of the present compound.

[A] _{D -3.27 (20t :, C = l.037} , H 2 0)

Elemental Ori值(as C ₇ H _ls fJ0 ₄₎

Calculation 值 (%) C: 47.45 H: 8.53 N: 7.90

Actual measurement () C 7.44 H-.8.51 N: 7.94

Example 2 N-ethyl-1-deoxygalata Tostatin Group Synthesis was carried out in the same manner as in Example 1 except that formalin was used instead of formalin. Break points 159 to 161t.

[N] _D -21.31 (20, C = l.032, H _a 0)

Elemental analysis II (as C _e H ₁₇ N0 *)

Calculation 值 (%) C: 50.25 H: 8.96 N:?. 32

Measured 值 (%) C: 49.96 H: 8.85 N: 7.31

Example 3 Synthesis of N—n-guchi Bil-1 11 Deoxygalactostatin

The synthesis was carried out in the same manner as in Example 1 using propionaldehyde instead of formalin. 120-122 t.

[A] _{D -27.00 (20:, C =} 0.985, H 2 0)

Elemental analysis 值 (C ₃ H ₁₃ N (as U)

Calculated value (%) C: 52.67 Η: 9.33 Ν: 6.82 Actual measurement (%) C: 52.52 H: 9.21 N: 6.87

Example 4 Synthesis of N-isoptyl-1-doxygalactostatin

It was synthesized in the same manner as in Example 1 using isobutanal instead of formalin, and crystallized as a hydrochloride. Melting point U2 ~ 145t ₀

[]! ) 1.93 (201, O0.516, H _a 0)

Elemental analysis plant (as C ₁₀ H ₂₁ N! H · HC1)

Calculation 揎 (%) C: 46.97 H: 8.67 N: 5.48

Measured planting (%) C 6.81 Η · 8.67 Ν: 5.46

Example 5 Synthesis of Ν-η-heptyl-1-deoxygalactostatin

Synthesis was carried out in the same manner as in Example 1 except that heptanal was used instead of formalin. Break point 125-127t.

(Α) _D -25.92 (20, C = l.003, MeOH)

Elemental analysis (as C _l3 H ₃₇ N0 *)

Calculated value (%) C: 59.74 H: 10.1 N: 5.36

Actual measurement (%) C: 59.25 H: 10.41 N: 5.37

Example 6 Synthesis of N—π-dodecyl-1-deoxygalactostatin

It was synthesized in the same manner as in Example 1 using dodecanal instead of formalin. Mp 124-128.

(Α) _D -14.41 (20t :, C = 0.999, D SO)

Elemental Analysis planting (as C _l8 H ₃₇ N0 ₄₎

Calculation 值 (%) C: 65.22 H: 11.25 N: 4.23 Actual measurement (%) C: 64.79 H: 10, 91 N: 4.22

Example 合成 Synthesis of N- (3-phenylpropyl) 1-1-doxygalactostatin

The synthesis was carried out in the same manner as in Example 1 except that 3-phenylbutane was used instead of formalin. Mp 100-104.

[A] _D -25.94 (20 :, C = 0.501. EOH)

Elemental analysis plant (as C, sH ₃₃ N04)

Calculation 楦 (%) C: 64.04 H: 8.24 N .98

Measured 值 (96) C: 64.01 H: 8.35 N: 5.02

Example 8 Synthesis of N-p-Cross Pencil 1-Doxyxygalactostatin

It was synthesized in the same manner as in Example 1 using p-clopentzaldehyde instead of formalin, and crystallized as a hydrochloride. Mp 101-104.

[] _D 12.59 (20 :, C = l.000, HaQ)

Elemental analysis 值 (as C _ls H ₂₃ N0 ΗΠ · 1 / 2Η ₂₀ )

Total 箅值 (%) C: 46.86 H: 6.05 N: 4.20

Measured value (%) C-.46.75 H: 6.22 N .13

Example 9 Synthesis of N-aryl-1-doxygalactostatin

1-Doxygalactostatin hydrochloride 0.3 g (1.5 mmol), non-permanent carbon dioxide rim 0.21 g (1.7 mmol) are suspended in DMF 5: £, and in ice cooling, 0.2 g of aryl bromide (1.65 mmol) Was added, and the mixture was stirred at room temperature for 12:00 K. After stirring, the salt was filtered off, and the mixture was subjected to resin treatment in the same manner as in Example 1 to give the present invention. 0.19 g of the compound was obtained. 144-146 t.

[URN] _{D -14.69 (20t :, C = l.007} , H a 0)

Elemental analysis value (as C _a H ₁₇ N0 *)

Calculation 楦 () C: 53.19 Η: 8.43 Ν: δ.89

Actual measurement (%) C: 53.00 H: 8.9 N: 6.79

Example 10 Synthesis of N-cinnamyl-1-dexoxygalactostatin

The synthesis was carried out in the same manner as in Example 9 except that cinnamyl bromide was used instead of the arylamide. 66-69 t.

(Α) _D -40.63 (20 * C, C = 0.507, MeOH)

Elemental analysis (as dsH ^ NO l / ^ HaO)

Calculation plant (%) C: 62.48 H: 7.69 N .86

Actual measurement (%) C: 62.56 H: 7.68 N .89

Example 11 Synthesis of N-methoxyl-nidoxygalactostatin

It was synthesized in the same manner as in Example 1 using acetate aldehyde. Melting point 110 ~ lllto

Ca _B -14.42 (201, C = l.040, H ₃₀ )

Elemental analysis (as C ₉ H _1S N0 ₅ )

Total (%) C 8.86 H: 8.66 N: 6.33

Measured value (%) C: 48.43 H: 8.83 N: 6.37

Example 12 Synthesis of N- (p-phenylpentyl) -11-doxygalactostatin

In the same manner as in Example 1 using phenylpentzaldehyde Synthesized. At the break point Vn ~ 178.

[N] _D -24.03 (20, C = 0.491, DHSD)

FAB-MAS m / z 330 (U + +1)

Elemental析值(as _{_{C ia H 33 N0 l / 4H}} 2 0)

Calculation 值 (%) C: 68.35 H: 7.09 NU.19

Measurement plant (%) C: 68.71 H: 7.35 NU.20

Example 13 Synthesis of N—n-pentylnylu-1-deoxygalatatostatin

The synthesis was performed in the same manner as in Example 1 except that π-pentanal was used instead of formalin. Breakpoints 115-116 :.

[Do] D -26.30 (at _{20, C = 0.517, H 2} 0)

Elemental analysis 值 (as C Hw! Ith)

Calculation 值 (%) C: 56.63 H: 9.94 Ν: 6000

Actual planting () C: 56.35 H: 9.63 Ν: 6.06

Example 14 Synthesis of N-p-methoxypentyl 1-deoxygalactostatin

The synthesis was carried out in the same manner as in Example 1 except that ρ-anisaldehyde was used instead of formalin. Mp 122-124.

[Α] D -26.62 (at 20, 00.586, Η ₈ 0)

PAB-MAS / z 284 (+ +1)

Elemental analysis (as C ₁₄ H ₂₁ Nih)

Total (%) C: 59.35 H: 7.47 N: 4.94

Actual measurement () C: 59.05 H: 7.43 N: 4.91

Example 15 N- (p-methylthiobenzyl) 1-1-doxy Synthesis of galactostatin

The synthesis was carried out in the same manner as in Example 1 except that p-methylthiobenzaldehyde was used instead of formalin. 120-123.

FAB-MAS ra / z 300 (U + +1)

As elemental析值_{_{(C 14 H 21 N0 «S}} · 1/2 H 3 0>

Calculated value () C: 54.52 H: 7.20 N: 4.54

Actual measurement (%) C: 54.38 H: 6.91 N: 4.72

Example 16 Synthesis of Huunylethyl; 71-doxygalactostatin

The synthesis was carried out in the same manner as in Example 1 except that phenylacetaldehyde was used instead of formalin. Melting point 188-190t.

PAB-MAS m / z 268 (M + +1)

Elemental析值(C> as 4H ₃₁ N04)

Calculated value (%) C: 62.90 H: 7.93 N: 5.24

Measured 值 (%) C: 62.57 H: 8.01 N: 5.32

Example 17 Synthesis of N- (1-dexoxygalactitol) 1-deoxygalactostatin

The synthesis was carried out in the same manner as in Example 1 except that D-galactose was used instead of formalin. Mp 79-82.

[A] _{D -17.60 (20:, 00.284,} H 3 0)

FAB-MAS ra / z 328 (+ +1)

Elemental analysis 值 (as C ₁₃ H _a5 N0 ₃ · 2H ₂₀ )

Calculation 值 (%) C: 39.6? H: 8.04 N: 3.85

Measured 值 (%) C: 39.70 H: 8.32 N: 4.15

Example 18 N— (p—methyl benzyl) Synthesis of cigaract tostatin

The synthesis was carried out in the same manner as in Example 1 except that p-acetaminopentaldehyde was used instead of formalin. With a melting point of 95-96. [<<] _D -20.73 (20: C = 0.492, H ₃₀ )

FAB-MAS m / z 311 (M ⁺ +1)

Elemental analysis (as _{_{_{_{C 15 H 32 N 3 0 5}}}} · 3 / 4H a 0)

Calculation 值 (%) C: 55.63 H: 7.31 N: 8.65

Measured value (%) C: 55.89 H: 7.55 N: 8.64

Example 19 Synthesis of N-phenylp-n-Bil-1-doxygalactostatin

The synthesis was carried out in the same manner as in Example 1 except for using L-nylpropanal instead of formalin. Breakpoints 100-104.

[<<] _D -25.94 (20 :, 00.501, MeOH)

PAB- AS m / z 282 ( ⁺ +1)

Elemental analysis (as Ci _S H _S3 N04)

Total planting (%) C-64.Q4 H: 8.24 N: 4.98

Measured value (%) C: 64.01 H: 8.35 N: 5.02

Example 20 Synthesis of N-cyclohexylmethyl-1-deoxygalatatostatin

The synthesis was carried out in the same manner as in Example 1 except that cyclohexanecarboxaldehyde was used instead of formalin. Breakpoints 72-73 :. [A] _D -39.72 (at 20, 00.715, H ₂ 0)

FAB-MAS ra / z 260 (M +1)

Elemental analysis (C _l3 H _as N [as K · 1 / 4Η ₃ 0)

Calculation 煊 (%) C: 59.18 H: 9.74 N: 5.31 Measured 楦 (%) C: 58.89 H: 9.77 N: 5.29

Example 21-Synthesis of (3'-methylthiopropyl) -11-deoxygalacto-statin

It was synthesized in the same manner as in Example 1 except that methylthiopropionaldehyde was used instead of formalin. 121-124 t. (A) _D -16.00 (20 * C, C = 0.550, H _a 0)

Elemental analysis value (C ₁₀ H ₂₁ N (as S ♦ l / 2H _a Q)

Calculated value (%) C: 46.13 H: 8.51 N: 5.38

Observed value (%) C: 46.11 H: 8.21 N: 5.30

Example 22 Synthesis of N _- (3′-methyl-2 4′-methoxypentyl) 1:}-doxygalactostatin

The synthesis was carried out in the same manner as in Example 1 except that 3-methyl-14-methoxybenzaldehyde was used instead of formalin. Melting point 185-187t.

FAB-MAS m / z 298 ( ⁺ +1)

Elemental analysis (as C, sH ₃₃ NQ _s )

Calculation 楦 (%) C: 60.59 H: 7.80 N: 4.71

Actual measurement (%) C: 60.48 H: 7.82 N: 4.66

Example 23 Synthesis of N—n-butyl-1-doxygalactostatin

The compound was synthesized in the same manner as in Example 9 except that η-butyl bromide was used instead of arylpromide. 121-123 t.

(Α) _D -23.90 (20, C = 0.502, H ₃₀ )

FAB-MAS m / z 220 (M + +1) Elemental析值(as _{_{_{C 10 H 21 N [] 4}}} )

Calculation plant (%) C: 54.77 H: 9.65 N: 6.39

Actual planting (%) C: 54.33 H: 9.56 N: 6.36

Example 24 Synthesis of N- (3-carboxyp-p-bil) -1-doxygalactostatin

The synthesis was carried out in the same manner as in Example 9 except that ethyl 3-bromobutionate was used instead of aryl bromide. Tori point 105 ~ 107 t: ₀

Ca] D 8.10 (201 :, C = 0.148, H _a 0)

PAB-MAS m / z 250 01 + +1)

Elemental析值(as dofhsNC · H ₈ Q)

Calculator (%) C: 44.94 H: 7.92 N: 5.24

Measured (%) C: 44.58 H: 7.97 N: 5.24

Test example

] 9-Galactosidase inhibitory activity

0-Nitrophenyl / 91-D-galactosylonase is used as a substrate, and 3-galactosidase is acted on. It was measured by That is, a solution containing lOOmM acid buffer 0.9m £ (pH 5.0) and a sample containing solution (dissolved in lOQmM drunk buffer pH 5.0) 0. A mixture of lm £ and 20mM substrate solution 0.5m at 37 for 5 minutes After simple preliminary heating, it was dissolved in ΙΟιηΜ acetate buffer pH 5.0. Next, 0.5 ml of j9-galactosidase solution was added and reacted at 37 t for 15 minutes. Then, the absorbance (A) at 420 mn was measured, and simultaneously the absorbance (B) of the reaction solution containing no sample was measured, and the inhibition rate was determined as (B-A) XB X The concentration (IC _S0 ) at which the β-potency lactosidase activity was inhibited by 50% was calculated. Table 1 shows the results of the two tests (Test Example 1 and Test Example 2). Incidentally, one galactosamine DOO oxidase is Ryo Aspergillus genus (Aspergirus sp.) _{Compound of the present invention was used from that, it is clear that to have a strong / S- galactosyltransferase preparative oxidase inhibitory activity. Table 1 9-galactosidase inhibition activity

Test example 1 Test example 2

Example ICso (ng / id) Example ICso (ng / id)

Number number

1 1 5 1 1 5 9

2 8 2 1 2 1 6 6

3 4 4 1 3 1 1 3

4 4 0 1 4 3 9 1

5 3 2 1 5 3 9 3

6 2 3 1 6 2 1

7 8 8 1 7 4 9

8 1 8 0 1 8 3 4 0

9 1 8 7 2 0 3 7

1 0 1 7 5 2 1 4 9

Control 2 2 3 5 9

(1-Doxy

タ ratatostatin 4 5 1

^ ai ^.) 2 3 1 5 4

2 4 3 5 1

Contrast

(1-Doxy

ί Ratatostati 4 4 0

Hydrochloride)

Claims

Scope of Claim West

1. The following general formula [I]

H

0 H

(In the formula, a saturated hydrocarbon or unsaturated chlorocarbon having 1 to 18 carbon atoms which may have a linear, branched or cyclic g 换 group is represented.) 3, 4, 5—Trihydroxybiperidine derivatives or pharmacologically acceptable salts thereof.